In previous studies we demonstrated that an efficient immunosurveillance mechanism ordinarily protects cats against development of leukemia-lymphoma following natural exposure to the feline leukemia virus (FeLV). This immune response is not directed to the FeLV itself, but rather to the feline oncornavirus-associated cell membrane antigen (FOCMA) which is probably the clearest example of a RNA tumor virus encoded tumor specific antigen. The humoral antibody response to FOCMA is clearly associated with protection against tumor development, and the antibodies to FOCMA are highly lytic in the presence of cat complement. We plan to test our "immunoselection hypothesis" which proposes that "virus-negative" tumors of cats (and possibly other species) may result from immune responses that are discordant between anti-viral and anti-tumor components. According to this hypothesis, an efficient anti-FLV gp 70 response in the absence of an adequate anti-FOCMA response would select for tumor clones that do not make virus. Other possible immune effector mechanisms, particularly NK activity, ADCC, and T cell immunity would be evaluated with the humoral response in a comparative sense using FOCMA on tumors of lymphoid, fibroblastoid (sarcoma), and epitheliod (melanoma) tumors as targets. Studies on the significance of histocompatibility antigens in virus neutralization will be continued in the human HLA (cell culture) system and initiated in the cat model. The NK system in the cat will be studied in relation to both FeLV and FOCMA targets, including the relationship of this system to genetic background and potentiation by interferon. Studies of mechanisms by which RNA tumor viruses interfere with the immune response will be continued. Of high priority will also be studies on the nature of the lymphoid cell target in the cat and the effect of the virion protein p15e on various parameters of lymphoid cell function. The antigenic nature of immune complexes observed in cases of persisting natural infections with FeLV will be evaluated.